Materiały źródłowe

• #1 Uterine Leiomyomata – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK546680/

  Uterine leiomyomata, also known as uterine fibroids, are the most common benign gynecologic tumors, occurring in 50% to 70% of females by menopause, with rates reaching over 80% in Black women. […] Leiomyomata originate from uterine smooth muscle cells in the myometrium, and their growth is primarily stimulated by circulating estrogen. […] Several molecular studies have identified specific gene mutations associated with leiomyomata, the most common of which is the MED12 gene located on chromosome X at position q13. […] The MED12 gene codes for one of the key proteins in the mediator complex (subunit 12) that regulates RNA polymerase II; a mutation in this gene occurs in approximately 70% of uterine leiomyomas. […] Additionally, uterine leiomyomata are hormonally sensitive tumors, and evidence has demonstrated that leiomyomas overexpress certain estrogen and progesterone receptors when compared to normal surrounding myometrium.

• #2 Uterine Fibroids Initiation and Pathogenesis | Endocrine Society

  https://www.endocrine.org/journals/endocrine-reviews/uterine-fibroids-initiation-and-pathogenesis

  Uterine fibroids are benign monoclonal neoplasms of the myometrium, representing the most common tumors in women worldwide. […] To date, no long-term or noninvasive treatment option exists for hormone-dependent uterine fibroids, due to the limited knowledge about the molecular mechanisms underlying the initiation and development of uterine fibroids. […] This paper comprehensively summarizes the recent research advances on uterine fibroids, focusing on risk factors, development origin, pathogenetic mechanisms, and treatment options. […] Deeper mechanistic insights into tumor etiology and the complexity of uterine fibroids can contribute to the progress of newer targeted therapies.

• #3 Uterine fibroids (leiomyomas): Histology and pathogenesis – UpToDate

  https://www.uptodate.com/contents/uterine-fibroids-leiomyomas-histology-and-pathogenesis

  Uterine fibroids (leiomyomas) are the most common pelvic neoplasm in females. They are nonmalignant monoclonal tumors arising from the smooth muscle cells of the myometrium. The pathogenesis of leiomyomas is not well understood. Genetic predisposition, environmental factors, steroid hormones, and growth factors important in fibrotic processes and angiogenesis all play a role in the formation and growth of uterine fibroids. […] Leiomyoma-related effects on the function and structure of the endometrium are the final common pathways in the pathogenesis of excessive bleeding in myomatous uteri, and there is evidence of both histologic changes in the endometrium and endometrial vasculature in these uteri. […] The pathogenesis of uterine leiomyomas is reviewed here. At least two distinct components contribute to leiomyoma development.

• #4 Uterine fibroids (leiomyomas): Histology and pathogenesis – UpToDate

  https://www.uptodate.com/contents/uterine-fibroids-leiomyomas-histology-and-pathogenesis/print

  Uterine fibroids (leiomyomas) are the most common pelvic neoplasm in females. They are nonmalignant monoclonal tumors arising from the smooth muscle cells of the myometrium. The pathogenesis of leiomyomas is not well understood. Genetic predisposition, environmental factors, steroid hormones, and growth factors important in fibrotic processes and angiogenesis all play a role in the formation and growth of uterine fibroids. […] The disease is heterogeneous, and different fibroids within the same uterus may have different etiologies and arise from different somatic mutations. […] Leiomyoma-related effects on the function and structure of the endometrium are the final common pathways in the pathogenesis of excessive bleeding in myomatous uteri, and there is evidence of both histologic changes in the endometrium and endometrial vasculature in these uteri. […] The pathogenesis of uterine leiomyomas is reviewed here. At least two distinct components contribute to leiomyoma development.

• #5 Uterine Fibroids: Pathogenesis and Interactions with Endometrium and Endomyometrial Junction

  https://pmc.ncbi.nlm.nih.gov/articles/PMC3791844/

  Uterine leiomyomas (fibroids or myomas) are benign tumors of uterus and clinically apparent in a large part of reproductive aged women. […] To date, several pathogenetic factors such as genetics, microRNA, steroids, growth factors, cytokines, chemokines, and extracellular matrix components have been implicated in the development and growth of leiomyoma. […] Nowadays, conflicting data about the pathogenesis of leiomyomas coexist in the literature. The development of uterine myomas can be linked to predisposing risk factors, initiators and genetic mechanisms, promoters, and effectors. […] Even if many risk factors suggested by epidemiologic studies have linked uterine leiomyomas to the effects of estrogens and progesterone levels and their metabolism, other mechanisms may be involved in fibroids pathogenesis.

• #6 Uterine Fibroids: Pathogenesis and Interactions with Endometrium and Endomyometrial Junction

  https://pmc.ncbi.nlm.nih.gov/articles/PMC3791844/

  The authors measured the growth of fibroids in black and white women with clinically relevant fibroids using MRI technology; they demonstrated that fibroids within the same woman often have different growth rates despite having a similar hormonal milieu. […] It has been generally accepted that myomas are more prevalent in blacks than in Caucasian and Hispanic populations. […] Recently, some authors reported a statistically significant inverse correlation between serum 25-(OH) Vit D levels and fibroid prevalence in black subjects. […] Leppert et al. reported that the pathogenesis of fibroids seems to involve a positive feedback loop between extracellular matrix production and cell proliferation, and vitamin D might act to block the positive feedback. […] Several theories about the initiators of fibroids have been proposed.

• #7 Uterine fibroid – Wikipedia

  https://en.wikipedia.org/wiki/Uterine_fibroid

  Fibroids are monoclonal tumors and approximately 4050% show karyotypically detectable chromosomal abnormalities. When multiple fibroids are present they frequently have unrelated genetic defects. Specific mutations of the MED12 protein have been noted in 70 percent of fibroids. […] The exact cause of fibroids is not clearly understood, but the current working hypothesis is that genetic predispositions, prenatal hormone exposure and the effects of hormones, growth factors and xenoestrogens cause fibroid growth. Known risk factors are African descent, obesity, polycystic ovary syndrome, diabetes, hypertension, and never having given birth. […] It is believed that estrogen and progesterone have a mitogenic effect on leiomyoma cells and also act by influencing (directly and indirectly) a large number of growth factors, cytokines and apoptotic factors as well as other hormones. Furthermore, the actions of estrogen and progesterone are modulated by the cross-talk between estrogen, progesterone and prolactin signaling which controls the expression of the respective nuclear receptors. It is believed that estrogen promotes growth by up-regulating IGF-1, EGFR, TGF-beta1, TGF-beta3 and PDGF, and promotes aberrant survival of leiomyoma cells by down-regulating p53, increasing expression of the anti-apoptotic factor PCP4 and antagonizing PPAR-gamma signaling. Progesterone is thought to promote the growth of leiomyoma through up-regulating EGF, TGF-beta1 and TGF-beta3, and promotes survival through up-regulating Bcl-2 expression and down-regulating TNF-alpha. Progesterone is believed to counteract growth by downregulating IGF-1.

• #8 New Insights into Molecular Pathogenesis of Uterine Fibroids: From the Lab to a Clinician-Friendly Review | IntechOpen

  https://www.intechopen.com/chapters/1165825

  Uterine fibroids (UFs) (also known as leiomyomas or myomas) are the most common form of benign uterine tumors, affecting 70-80% of women over their lifetime. […] It has been hypothesized that leiomyomas arise from clonal proliferation of a single myometrial cell due to an initial genetic insult. However, these early cytogenetic alterations are insufficient for tumor development. In recent years, many advances have been made in the understanding of molecular mechanisms underlying the pathogenesis of uterine fibroids, and aberrations in several complex signaling pathways have shown to be involved in myoma development. […] Leiomyomas are monoclonal tumors that arise from uterine smooth muscle (i.e., the myometrium). […] Despite their high prevalence, the exact pathophysiology of uterine myomas is still unknown, although ethnicity-related data seem to indicate that the prevalence is about three times higher in African-American women.

• #9 Uterine Fibroids: Pathogenesis and Interactions with Endometrium and Endomyometrial Junction

  https://pmc.ncbi.nlm.nih.gov/articles/PMC3791844/

  The authors measured the growth of fibroids in black and white women with clinically relevant fibroids using MRI technology; they demonstrated that fibroids within the same woman often have different growth rates despite having a similar hormonal milieu. […] It has been generally accepted that myomas are more prevalent in blacks than in Caucasian and Hispanic populations. […] Recently, some authors reported a statistically significant inverse correlation between serum 25-(OH) Vit D levels and fibroid prevalence in black subjects. […] Leppert et al. reported that the pathogenesis of fibroids seems to involve a positive feedback loop between extracellular matrix production and cell proliferation, and vitamin D might act to block the positive feedback. […] Several theories about the initiators of fibroids have been proposed.

• #10 Uterine fibroid – Wikipedia

  https://en.wikipedia.org/wiki/Uterine_fibroid

  Fibroids are monoclonal tumors and approximately 4050% show karyotypically detectable chromosomal abnormalities. When multiple fibroids are present they frequently have unrelated genetic defects. Specific mutations of the MED12 protein have been noted in 70 percent of fibroids. […] The exact cause of fibroids is not clearly understood, but the current working hypothesis is that genetic predispositions, prenatal hormone exposure and the effects of hormones, growth factors and xenoestrogens cause fibroid growth. Known risk factors are African descent, obesity, polycystic ovary syndrome, diabetes, hypertension, and never having given birth. […] It is believed that estrogen and progesterone have a mitogenic effect on leiomyoma cells and also act by influencing (directly and indirectly) a large number of growth factors, cytokines and apoptotic factors as well as other hormones. Furthermore, the actions of estrogen and progesterone are modulated by the cross-talk between estrogen, progesterone and prolactin signaling which controls the expression of the respective nuclear receptors. It is believed that estrogen promotes growth by up-regulating IGF-1, EGFR, TGF-beta1, TGF-beta3 and PDGF, and promotes aberrant survival of leiomyoma cells by down-regulating p53, increasing expression of the anti-apoptotic factor PCP4 and antagonizing PPAR-gamma signaling. Progesterone is thought to promote the growth of leiomyoma through up-regulating EGF, TGF-beta1 and TGF-beta3, and promotes survival through up-regulating Bcl-2 expression and down-regulating TNF-alpha. Progesterone is believed to counteract growth by downregulating IGF-1.

• #11 A COMPREHENSIVE REVIEW OF UTERINE FIBROIDS: PATHOGENESIS, DIAGNOSIS, TREATMENT, AND FUTURE PERSPECTIVES | Journal of Population Therapeutics and Clinical Pharmacology

  https://www.jptcp.com/index.php/jptcp/article/view/3385

  Fibroid, myoma, and leiomyoma are interchangeable terms used to describe the most common gynecological tumors, which are benign neoplasms originating in the smooth muscles of the uterus. […] Age and race are the primary risk factors for uterine fibroids, with African American women experiencing higher incidence rates compared to Caucasian women. A family history of uterine fibroids also increases the risk of developing them. […] Lifestyle factors such as obesity, dietary choices, sedentary living, and smoking have been linked to fibroid occurrence, possibly due to their influence on estrogen production. […] Stress may also be a contributing risk factor for fibroids, as it is associated with a higher body mass index. […] A diet rich in red meat has been connected to a 70% increased risk of fibroids. […] It’s worth noting that large fibroids can impact the uterine cavity’s configuration, potentially affecting embryo implantation and increasing the risk of miscarriage.

• #12 A COMPREHENSIVE REVIEW OF UTERINE FIBROIDS: PATHOGENESIS, DIAGNOSIS, TREATMENT, AND FUTURE PERSPECTIVES | Journal of Population Therapeutics and Clinical Pharmacology

  https://www.jptcp.com/index.php/jptcp/article/view/3385

  Fibroid, myoma, and leiomyoma are interchangeable terms used to describe the most common gynecological tumors, which are benign neoplasms originating in the smooth muscles of the uterus. […] Age and race are the primary risk factors for uterine fibroids, with African American women experiencing higher incidence rates compared to Caucasian women. A family history of uterine fibroids also increases the risk of developing them. […] Lifestyle factors such as obesity, dietary choices, sedentary living, and smoking have been linked to fibroid occurrence, possibly due to their influence on estrogen production. […] Stress may also be a contributing risk factor for fibroids, as it is associated with a higher body mass index. […] A diet rich in red meat has been connected to a 70% increased risk of fibroids. […] It’s worth noting that large fibroids can impact the uterine cavity’s configuration, potentially affecting embryo implantation and increasing the risk of miscarriage.

• #13 Uterine fibroid – Wikipedia

  https://en.wikipedia.org/wiki/Uterine_fibroid

  Fibroids are monoclonal tumors and approximately 4050% show karyotypically detectable chromosomal abnormalities. When multiple fibroids are present they frequently have unrelated genetic defects. Specific mutations of the MED12 protein have been noted in 70 percent of fibroids. […] The exact cause of fibroids is not clearly understood, but the current working hypothesis is that genetic predispositions, prenatal hormone exposure and the effects of hormones, growth factors and xenoestrogens cause fibroid growth. Known risk factors are African descent, obesity, polycystic ovary syndrome, diabetes, hypertension, and never having given birth. […] It is believed that estrogen and progesterone have a mitogenic effect on leiomyoma cells and also act by influencing (directly and indirectly) a large number of growth factors, cytokines and apoptotic factors as well as other hormones. Furthermore, the actions of estrogen and progesterone are modulated by the cross-talk between estrogen, progesterone and prolactin signaling which controls the expression of the respective nuclear receptors. It is believed that estrogen promotes growth by up-regulating IGF-1, EGFR, TGF-beta1, TGF-beta3 and PDGF, and promotes aberrant survival of leiomyoma cells by down-regulating p53, increasing expression of the anti-apoptotic factor PCP4 and antagonizing PPAR-gamma signaling. Progesterone is thought to promote the growth of leiomyoma through up-regulating EGF, TGF-beta1 and TGF-beta3, and promotes survival through up-regulating Bcl-2 expression and down-regulating TNF-alpha. Progesterone is believed to counteract growth by downregulating IGF-1.

• #14 Pathogenesis, Classification, Histopathology, and Symptomatology of Fibroids | Obgyn Key

  https://obgynkey.com/pathogenesis-classification-histopathology-and-symptomatology-of-fibroids/

  Matrix metalloproteinases (MMPs) are implicated in fibroid remodeling with a higher activity of MMP-2 in fibroids than in surrounding myometrium. […] This means that the tumor microenvironment may greatly influence tumor growth and proliferation. […] The genetic background seems to play an important role, with cytogenetic anomalies observed in about 40% of uterine fibroids. […] Abnormal ECM expression, increased growth factors, cytokine and chemokine concentrations, and an extracellular disorganized matrix have been implicated in development and growth of uterine fibroids. […] Estrogens may exert their growth stimulatory effects on such tumors through the action of a complex network of cytokines, growth factors, or apoptosis factors and through different cellular mechanisms. […] Biochemical and clinical studies also suggested that progesterone, progestin, and progesterone receptors (PR-A and PR-B) might increase proliferative activity in fibroids by enhancing the expression of growth factors (EGF, IGF-I) and apoptosis-related factors (TNF alpha, Bcl-2 proteins).

• #15 Uterine fibroids (leiomyomas): Histology and pathogenesis – UpToDate

  https://www.uptodate.com/contents/uterine-fibroids-leiomyomas-histology-and-pathogenesis/print

  Uterine fibroids (leiomyomas) are the most common pelvic neoplasm in females. They are nonmalignant monoclonal tumors arising from the smooth muscle cells of the myometrium. The pathogenesis of leiomyomas is not well understood. Genetic predisposition, environmental factors, steroid hormones, and growth factors important in fibrotic processes and angiogenesis all play a role in the formation and growth of uterine fibroids. […] The disease is heterogeneous, and different fibroids within the same uterus may have different etiologies and arise from different somatic mutations. […] Leiomyoma-related effects on the function and structure of the endometrium are the final common pathways in the pathogenesis of excessive bleeding in myomatous uteri, and there is evidence of both histologic changes in the endometrium and endometrial vasculature in these uteri. […] The pathogenesis of uterine leiomyomas is reviewed here. At least two distinct components contribute to leiomyoma development.

• #16 Uterine Fibroids: Pathogenesis and Interactions with Endometrium and Endomyometrial Junction

  https://pmc.ncbi.nlm.nih.gov/articles/PMC3791844/

  Another interesting theory underlines that the pathogenesis might be similar to a response to injury; ischemic damage could be linked to release of increased vasoconstrictive substances at the time of the menses. […] Historically, uterine leiomyomata have not been considered a genetic disease. However much recent clinical evidence indicates that at least some myomata have a genetic etiology. […] Recent studies described that 70% of fibroids contained a series of mutations in a transcriptional regulator complex subunit 12 (MED12). […] Research for the pathogenesis of fibroids and abnormal extracellular matrix (ECM) led to the analysis of a growth factor with profibrotic activity, transforming growth factor (TGF-). […] Epigenetic changes have also been implicated in leiomyoma formation.

• #17 Uterine Leiomyomata – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK546680/

  Uterine leiomyomata, also known as uterine fibroids, are the most common benign gynecologic tumors, occurring in 50% to 70% of females by menopause, with rates reaching over 80% in Black women. […] Leiomyomata originate from uterine smooth muscle cells in the myometrium, and their growth is primarily stimulated by circulating estrogen. […] Several molecular studies have identified specific gene mutations associated with leiomyomata, the most common of which is the MED12 gene located on chromosome X at position q13. […] The MED12 gene codes for one of the key proteins in the mediator complex (subunit 12) that regulates RNA polymerase II; a mutation in this gene occurs in approximately 70% of uterine leiomyomas. […] Additionally, uterine leiomyomata are hormonally sensitive tumors, and evidence has demonstrated that leiomyomas overexpress certain estrogen and progesterone receptors when compared to normal surrounding myometrium.

• #18 Uterine Leiomyomata – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK546680/

  Uterine leiomyomata, also known as uterine fibroids, are the most common benign gynecologic tumors, occurring in 50% to 70% of females by menopause, with rates reaching over 80% in Black women. […] Leiomyomata originate from uterine smooth muscle cells in the myometrium, and their growth is primarily stimulated by circulating estrogen. […] Several molecular studies have identified specific gene mutations associated with leiomyomata, the most common of which is the MED12 gene located on chromosome X at position q13. […] The MED12 gene codes for one of the key proteins in the mediator complex (subunit 12) that regulates RNA polymerase II; a mutation in this gene occurs in approximately 70% of uterine leiomyomas. […] Additionally, uterine leiomyomata are hormonally sensitive tumors, and evidence has demonstrated that leiomyomas overexpress certain estrogen and progesterone receptors when compared to normal surrounding myometrium.

• #19 RISING STARS: Role of MED12 mutation in the pathogenesis of uterine fibroids in: Journal of Molecular Endocrinology Volume 71 Issue 4 (2023)

  https://jme.bioscientifica.com/view/journals/jme/71/4/JME-23-0039.xml

  Uterine fibroids (UFs) are benign tumors arising from the uterus, characterized by accumulation of abundant extracellular matrix (ECM) and sex steroid-dependent growth. […] Among the driver gene mutations identified in UFs, mutations in MED12, a component of the cyclin-dependent kinase (CDK) Mediator module, are the most common and observed in 50-80% of UFs. […] MED12 mutation-positive UFs (MED12-UFs) often develop multiple rather than solitary and have distinct gene expression profiles, DNA methylomes, transcriptomes, and proteomes. […] Gene expressions related to ECM organization and collagen-rich ECM components are upregulated, and impaired Mediator kinase activity and dysregulation of Wnt/-catenin signaling are identified in MED12-UFs. […] Understanding of characteristics of MED12-UFs and functions of MED12 mutations for UF tumorigenesis may elucidate the pathophysiology of UFs, leading to the development of new therapeutic options in women with symptomatic UFs.

• #20 Vascular biology of uterine fibroids: connecting fibroids and vascular disorders in: Reproduction Volume 162 Issue 2 (2021)

  https://rep.bioscientifica.com/view/journals/rep/162/2/REP-21-0087.xml

  Genetic changes causally related to the development of approximately 90% of fibroids include alterations in signaling involving the mediator subcomplex 12 (MED-12) and high mobility group protein (HMGA)1 and 2 genes. […] While MED12 mutation does not vary with patient age and race but does correlate with smaller tumors and more numerous tumors. […] Rearrangements leading to overexpression of HMGA1 and HMGA2 mRNA have been observed in fibroids, likely influencing tumor growth via direct promotion of proliferation and indirectly via upregulation of angiogenesis. […] Apart from direct genetic mutations, epigenetic modifications and non-coding RNAs have been implicated in fibroid biology. […] Estradiol and progesterone are also synergistically involved in fibroid development. […] Estradiol stimulates estrogen receptors on uterine fibroblasts and promotes fibroblast proliferation and extracellular membrane production through fibroblast activation protein (FAP), MAP kinase activation, and activation of the PI3K-Akt-mTOR pathway in vitro.

• #21 Pathogenesis, Classification, Histopathology, and Symptomatology of Fibroids | Obgyn Key

  https://obgynkey.com/pathogenesis-classification-histopathology-and-symptomatology-of-fibroids/

  Uterine fibroid cells typically show a high expression of cell-cycle regulator and anti-apoptotic proteins. […] This can trigger tumor growth and make cells resistant to apoptosis. […] Somatic mutations involving the gene encoding the mediator complex subunit 12 (MED12) and the gene encoding the high-mobility group AT-hook 2 (HMGA2) are known to be associated to fibroids. […] The role of the wingless-type (Wnt) pathway in supporting tumor initiation of fibroids is well demonstrated. […] Other studies have demonstrated a central role for the phosphoinositide 3-kinaseprotein kinase B/AKT (PI3K/AKT) pathway leading to the activation of mammalian target of rapamycin (mTOR) in the pathogenesis of fibroids.

• #22 Uterine Leiomyomata – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK546680/

  Uterine leiomyomata, also known as uterine fibroids, are the most common benign gynecologic tumors, occurring in 50% to 70% of females by menopause, with rates reaching over 80% in Black women. […] Leiomyomata originate from uterine smooth muscle cells in the myometrium, and their growth is primarily stimulated by circulating estrogen. […] Several molecular studies have identified specific gene mutations associated with leiomyomata, the most common of which is the MED12 gene located on chromosome X at position q13. […] The MED12 gene codes for one of the key proteins in the mediator complex (subunit 12) that regulates RNA polymerase II; a mutation in this gene occurs in approximately 70% of uterine leiomyomas. […] Additionally, uterine leiomyomata are hormonally sensitive tumors, and evidence has demonstrated that leiomyomas overexpress certain estrogen and progesterone receptors when compared to normal surrounding myometrium.

• #23 Uterine Leiomyomata – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK546680/

  Studies indicate that the ovarian steroids estradiol and progesterone promote the growth of leiomyomas, and myometrial cells with high levels of estrogen and progesterone receptors can stimulate the growth of adjacent uterine leiomyomata stem cells in a paracrine fashion. […] The exact initiating factor of fibroid formation remains unclear. However, prevailing theories highlight the role of reproductive hormones, inherent abnormalities of the myometrium, and predisposing genetic variations that affect cell signaling pathways.

• #24 Uterine Leiomyomata – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK546680/

  Uterine leiomyomata, also known as uterine fibroids, are the most common benign gynecologic tumors, occurring in 50% to 70% of females by menopause, with rates reaching over 80% in Black women. […] Leiomyomata originate from uterine smooth muscle cells in the myometrium, and their growth is primarily stimulated by circulating estrogen. […] Several molecular studies have identified specific gene mutations associated with leiomyomata, the most common of which is the MED12 gene located on chromosome X at position q13. […] The MED12 gene codes for one of the key proteins in the mediator complex (subunit 12) that regulates RNA polymerase II; a mutation in this gene occurs in approximately 70% of uterine leiomyomas. […] Additionally, uterine leiomyomata are hormonally sensitive tumors, and evidence has demonstrated that leiomyomas overexpress certain estrogen and progesterone receptors when compared to normal surrounding myometrium.

• #25 Uterine-Fibroids | Calgary Guide

  https://calgaryguide.ucalgary.ca/uterine-fibroids-leiomyomas-pathogenesis-and-clinical-findings/uterine-fibroids_final/

  Uterine Fibroids (Leiomyomas): Pathogenesis and clinical findings […] Estrogen stimulates proliferation of uterine smooth muscle cells […] Benign proliferation of monoclonal myometrial (uterine wall/muscle) cells into discrete masses […] Transformation of normal myocytes into abnormal myocytes […] Fibroids can be located in different areas of the uterus, including the following locations […] Subserosal Fibroid grows adjacent to perimetrium into uterine muscle […] Submucosal Fibroid grows adjacent to endometrium into uterine muscle […] Intramural Fibroid is within the thickness of the myometrium […] Pedunculated Fibroid extends into pelvic cavity or uterine cavity on a stalk […] Embryo cannot implant […] Infertility and/or recurrent pregnancy loss.

• #26 Pathogenesis, Classification, Histopathology, and Symptomatology of Fibroids | Obgyn Key

  https://obgynkey.com/pathogenesis-classification-histopathology-and-symptomatology-of-fibroids/

  Matrix metalloproteinases (MMPs) are implicated in fibroid remodeling with a higher activity of MMP-2 in fibroids than in surrounding myometrium. […] This means that the tumor microenvironment may greatly influence tumor growth and proliferation. […] The genetic background seems to play an important role, with cytogenetic anomalies observed in about 40% of uterine fibroids. […] Abnormal ECM expression, increased growth factors, cytokine and chemokine concentrations, and an extracellular disorganized matrix have been implicated in development and growth of uterine fibroids. […] Estrogens may exert their growth stimulatory effects on such tumors through the action of a complex network of cytokines, growth factors, or apoptosis factors and through different cellular mechanisms. […] Biochemical and clinical studies also suggested that progesterone, progestin, and progesterone receptors (PR-A and PR-B) might increase proliferative activity in fibroids by enhancing the expression of growth factors (EGF, IGF-I) and apoptosis-related factors (TNF alpha, Bcl-2 proteins).

• #27 Uterine fibroid – Wikipedia

  https://en.wikipedia.org/wiki/Uterine_fibroid

  Fibroids are monoclonal tumors and approximately 4050% show karyotypically detectable chromosomal abnormalities. When multiple fibroids are present they frequently have unrelated genetic defects. Specific mutations of the MED12 protein have been noted in 70 percent of fibroids. […] The exact cause of fibroids is not clearly understood, but the current working hypothesis is that genetic predispositions, prenatal hormone exposure and the effects of hormones, growth factors and xenoestrogens cause fibroid growth. Known risk factors are African descent, obesity, polycystic ovary syndrome, diabetes, hypertension, and never having given birth. […] It is believed that estrogen and progesterone have a mitogenic effect on leiomyoma cells and also act by influencing (directly and indirectly) a large number of growth factors, cytokines and apoptotic factors as well as other hormones. Furthermore, the actions of estrogen and progesterone are modulated by the cross-talk between estrogen, progesterone and prolactin signaling which controls the expression of the respective nuclear receptors. It is believed that estrogen promotes growth by up-regulating IGF-1, EGFR, TGF-beta1, TGF-beta3 and PDGF, and promotes aberrant survival of leiomyoma cells by down-regulating p53, increasing expression of the anti-apoptotic factor PCP4 and antagonizing PPAR-gamma signaling. Progesterone is thought to promote the growth of leiomyoma through up-regulating EGF, TGF-beta1 and TGF-beta3, and promotes survival through up-regulating Bcl-2 expression and down-regulating TNF-alpha. Progesterone is believed to counteract growth by downregulating IGF-1.

• #28

  https://link.springer.com/article/10.1007/s13669-012-0008-5

  Further, estrogen concentration in myoma tissue is greater than in the surrounding myometrium. Some studies have shown that leiomyoma tissues are a source of estrogen. […] Leiomyoma cells express an estrogen synthetase as well as aromatase and convert circulating androgens to estrogen. […] Estrogen secreted by leiomyoma tissue may reach a sufficient concentration within the local compartment to support its own growth, allowing independence from ovarian estrogen. […] Increased COMT activity is associated with increased estrogen levels and increased uterine fibroid growth. […] It has been reported that COMT expression is higher in uterine fibroid than in normal myometrium. […] Compared with the surrounding endometrium, uterine myoma has a high concentration of progesterone receptors.

• #29

  https://link.springer.com/article/10.1007/s13669-012-0008-5

  Further, estrogen concentration in myoma tissue is greater than in the surrounding myometrium. Some studies have shown that leiomyoma tissues are a source of estrogen. […] Leiomyoma cells express an estrogen synthetase as well as aromatase and convert circulating androgens to estrogen. […] Estrogen secreted by leiomyoma tissue may reach a sufficient concentration within the local compartment to support its own growth, allowing independence from ovarian estrogen. […] Increased COMT activity is associated with increased estrogen levels and increased uterine fibroid growth. […] It has been reported that COMT expression is higher in uterine fibroid than in normal myometrium. […] Compared with the surrounding endometrium, uterine myoma has a high concentration of progesterone receptors.

• #30 Progesterone Signaling and Uterine Fibroid Pathogenesis; Molecular Mechanisms and Potential Therapeutics

  https://www.mdpi.com/2073-4409/12/8/1117

  Although the leading causes of fibroids are unknown, accumulating epidemiological, clinical, and experimental evidence supports the pivotal role of ovarian steroid hormones in the growth and pathogenesis of UFs. […] Importantly, progesterone action is complex and involves interaction with receptors, transcription factors, kinase proteins, growth factors, and numerous autocrine and paracrine factors. […] The promising results of utilizing selective progesterone receptor modulators (SPRM) in controlling UF-associated symptoms such as bleeding as well as tumor shrinkage, further supports the role progesterone plays in UF pathogenesis. […] Disrupted progesterone signaling is causally linked to many reproductive diseases that result in subfertility or infertility, including UF. […] Studies demonstrated that progesterone signaling promotes the growth and proliferation of fibroid cells through increasing proliferating cell nuclear antigen (PCNA) expression, which increases both the number of fibroid cells and the size of fibroid tumors.

• #31 Progesterone Signaling and Uterine Fibroid Pathogenesis; Molecular Mechanisms and Potential Therapeutics

  https://www.mdpi.com/2073-4409/12/8/1117

  Progesterone has been shown to suppress apoptosis in fibroid cells, which may contribute more to the growth of UFs via B-cell lymphoma- (Bcl-) 2 protein expression induction than myometrium. […] Progesterone has been shown to modulate the production of cytokines such as TNF-α and IL-6. […] The findings of Liu et al. suggested that DNA methylation and MED12 mutation together constitute a complex regulatory network that affects progesterone/PR-mediated RANKL gene expression, with an essential role in activating stem cell proliferation and fibroid tumor development. […] Since the formation of new blood vessels is vital for the delivery of nutrients and oxygen to the growing tumors, progesterone may promote angiogenesis through the upregulation of VEGF which stimulates the growth of blood vessels.

• #32 Uterine fibroid – Wikipedia

  https://en.wikipedia.org/wiki/Uterine_fibroid

  Fibroids are monoclonal tumors and approximately 4050% show karyotypically detectable chromosomal abnormalities. When multiple fibroids are present they frequently have unrelated genetic defects. Specific mutations of the MED12 protein have been noted in 70 percent of fibroids. […] The exact cause of fibroids is not clearly understood, but the current working hypothesis is that genetic predispositions, prenatal hormone exposure and the effects of hormones, growth factors and xenoestrogens cause fibroid growth. Known risk factors are African descent, obesity, polycystic ovary syndrome, diabetes, hypertension, and never having given birth. […] It is believed that estrogen and progesterone have a mitogenic effect on leiomyoma cells and also act by influencing (directly and indirectly) a large number of growth factors, cytokines and apoptotic factors as well as other hormones. Furthermore, the actions of estrogen and progesterone are modulated by the cross-talk between estrogen, progesterone and prolactin signaling which controls the expression of the respective nuclear receptors. It is believed that estrogen promotes growth by up-regulating IGF-1, EGFR, TGF-beta1, TGF-beta3 and PDGF, and promotes aberrant survival of leiomyoma cells by down-regulating p53, increasing expression of the anti-apoptotic factor PCP4 and antagonizing PPAR-gamma signaling. Progesterone is thought to promote the growth of leiomyoma through up-regulating EGF, TGF-beta1 and TGF-beta3, and promotes survival through up-regulating Bcl-2 expression and down-regulating TNF-alpha. Progesterone is believed to counteract growth by downregulating IGF-1.

• #33 Progesterone Signaling and Uterine Fibroid Pathogenesis; Molecular Mechanisms and Potential Therapeutics

  https://www.mdpi.com/2073-4409/12/8/1117

  Although the leading causes of fibroids are unknown, accumulating epidemiological, clinical, and experimental evidence supports the pivotal role of ovarian steroid hormones in the growth and pathogenesis of UFs. […] Importantly, progesterone action is complex and involves interaction with receptors, transcription factors, kinase proteins, growth factors, and numerous autocrine and paracrine factors. […] The promising results of utilizing selective progesterone receptor modulators (SPRM) in controlling UF-associated symptoms such as bleeding as well as tumor shrinkage, further supports the role progesterone plays in UF pathogenesis. […] Disrupted progesterone signaling is causally linked to many reproductive diseases that result in subfertility or infertility, including UF. […] Studies demonstrated that progesterone signaling promotes the growth and proliferation of fibroid cells through increasing proliferating cell nuclear antigen (PCNA) expression, which increases both the number of fibroid cells and the size of fibroid tumors.

• #34 Progesterone Signaling and Uterine Fibroid Pathogenesis; Molecular Mechanisms and Potential Therapeutics

  https://www.mdpi.com/2073-4409/12/8/1117

  Although the leading causes of fibroids are unknown, accumulating epidemiological, clinical, and experimental evidence supports the pivotal role of ovarian steroid hormones in the growth and pathogenesis of UFs. […] Importantly, progesterone action is complex and involves interaction with receptors, transcription factors, kinase proteins, growth factors, and numerous autocrine and paracrine factors. […] The promising results of utilizing selective progesterone receptor modulators (SPRM) in controlling UF-associated symptoms such as bleeding as well as tumor shrinkage, further supports the role progesterone plays in UF pathogenesis. […] Disrupted progesterone signaling is causally linked to many reproductive diseases that result in subfertility or infertility, including UF. […] Studies demonstrated that progesterone signaling promotes the growth and proliferation of fibroid cells through increasing proliferating cell nuclear antigen (PCNA) expression, which increases both the number of fibroid cells and the size of fibroid tumors.

• #35 Progesterone Signaling and Uterine Fibroid Pathogenesis; Molecular Mechanisms and Potential Therapeutics

  https://www.mdpi.com/2073-4409/12/8/1117

  Although the leading causes of fibroids are unknown, accumulating epidemiological, clinical, and experimental evidence supports the pivotal role of ovarian steroid hormones in the growth and pathogenesis of UFs. […] Importantly, progesterone action is complex and involves interaction with receptors, transcription factors, kinase proteins, growth factors, and numerous autocrine and paracrine factors. […] The promising results of utilizing selective progesterone receptor modulators (SPRM) in controlling UF-associated symptoms such as bleeding as well as tumor shrinkage, further supports the role progesterone plays in UF pathogenesis. […] Disrupted progesterone signaling is causally linked to many reproductive diseases that result in subfertility or infertility, including UF. […] Studies demonstrated that progesterone signaling promotes the growth and proliferation of fibroid cells through increasing proliferating cell nuclear antigen (PCNA) expression, which increases both the number of fibroid cells and the size of fibroid tumors.

• #36 Pathophysiology of uterine fibroids

  https://www.contemporaryobgyn.net/view/pathophysiology-of-uterine-fibroids

  A better understanding of the pathophysiology of uterine fibroids (UFs) will enable healthcare providers to deliver high-quality informed care to their patients, according to Ayman Al-Hendy, MD, PhD, a professor of ob/gyn at Pritzker School of Medicine, University of Chicago. […] Pathophysiology also enables providers to understand the mechanism of action of the various treatment tools, so they can tailor and match an appropriate treatment to a specific patient, Al-Hendy told Contemporary OB/GYN. […] The key pathways are estrogen, progesterone, DNA damage, transforming growth factor beta, growth factors, the canonical Wnt pathway and extracellular matrix (ECM) remodeling. […] But we have limited safe treatment options for fibroid patients who want to preserve their fertility potential, Al-Hendy said. We also do not understand how fibroids cause heavy menstrual bleeding or infertility. […] Investigating genetic correlations and shared loci sheds light on potential causal relationships between reproductive traits and uterine leiomyomata, offering insights into their complex interplay and urging further mechanistic exploration.

• #37 Uterine fibroids: the role of signaling pathways in the pathogenesis. A literature review – Yarmolinskaya – Journal of obstetrics and women’s diseases

  https://journals.eco-vector.com/jowd/article/view/41926/en_US

  Uterine fibroids are one of the most common benign tumors of the female reproductive system, originating from smooth muscle cells of the cervix or uterine body. […] To date, there is no single and unambiguous opinion on the causes of the onset and recurrence of uterine fibroids, but thanks to the modern level of molecular medicine, much progress has been made in the study of hormonal and molecular genetic mechanisms of the initiation, formation and growth of the myoma node. […] This review presents modern data on the role of sex steroid hormones and their enzyme regulation, as well as growth factors and vitamin D in the pathogenesis of the disease. […] It was noted that the activation of signaling pathways such as Wnt / -catenin, MAPK / ERK, and TGF- / SMAD plays a significant role in the development of uterine fibroids. […] Further study of the pathogenesis of the disease is needed for new strategies to design targeted therapy of uterine leiomyoma.

• #38 RISING STARS: Role of MED12 mutation in the pathogenesis of uterine fibroids in: Journal of Molecular Endocrinology Volume 71 Issue 4 (2023)

  https://jme.bioscientifica.com/view/journals/jme/71/4/JME-23-0039.xml

  In vitro experiments using immortalized human myometrial smooth muscle cells overexpressing either wild-type MED12 or MED12 variant (c.131GA), which is the most common mutation observed in UFs, revealed that protein expression levels of Wnt4 and -catenin increased and the cell cycle progressed in the MED12 variant-overexpressing cells. […] These results indicate that the Med12 missense c.131GA variant acts as a gain-of-function mutation in the uterus of mice. […] The Wnt/-catenin signaling pathway is evolutionarily conserved in mammals and regulates diverse developmental processes, including proliferation, differentiation, apoptosis, migration, invasion, and tissue metabolism and homeostasis. […] The dysregulation of Wnt/-catenin signaling pathway plays important roles for the growth and maintenance of MED12-UFs.

• #39 RISING STARS: Role of MED12 mutation in the pathogenesis of uterine fibroids in: Journal of Molecular Endocrinology Volume 71 Issue 4 (2023)

  https://jme.bioscientifica.com/view/journals/jme/71/4/JME-23-0039.xml

  In vitro experiments using immortalized human myometrial smooth muscle cells overexpressing either wild-type MED12 or MED12 variant (c.131GA), which is the most common mutation observed in UFs, revealed that protein expression levels of Wnt4 and -catenin increased and the cell cycle progressed in the MED12 variant-overexpressing cells. […] These results indicate that the Med12 missense c.131GA variant acts as a gain-of-function mutation in the uterus of mice. […] The Wnt/-catenin signaling pathway is evolutionarily conserved in mammals and regulates diverse developmental processes, including proliferation, differentiation, apoptosis, migration, invasion, and tissue metabolism and homeostasis. […] The dysregulation of Wnt/-catenin signaling pathway plays important roles for the growth and maintenance of MED12-UFs.

• #40 New Insights into Molecular Pathogenesis of Uterine Fibroids: From the Lab to a Clinician-Friendly Review | IntechOpen

  https://www.intechopen.com/chapters/1165825

  The presence of steroid hormones stimulates the secretion of Wnt ligands from mature myometrium or leiomyoma cells. […] The activation of canonical Wnt pathway (-catenin-dependent) stimulates the differentiation of resting fibroblasts into myofibroblasts and has a key role in fibrotic processes, such as myoma development. […] In summary, molecular events in myoma biology are regulated through a complex network of interconnected and convergent, intracellular, extracellular, and intercellular pathways. Each pathway does not work on its own but it is a complicated network of molecular processes, although several signal transduction pathways converge into a final pathway.

• #41 New Insights into Molecular Pathogenesis of Uterine Fibroids: From the Lab to a Clinician-Friendly Review | IntechOpen

  https://www.intechopen.com/chapters/1165825

  The presence of steroid hormones stimulates the secretion of Wnt ligands from mature myometrium or leiomyoma cells. […] The activation of canonical Wnt pathway (-catenin-dependent) stimulates the differentiation of resting fibroblasts into myofibroblasts and has a key role in fibrotic processes, such as myoma development. […] In summary, molecular events in myoma biology are regulated through a complex network of interconnected and convergent, intracellular, extracellular, and intercellular pathways. Each pathway does not work on its own but it is a complicated network of molecular processes, although several signal transduction pathways converge into a final pathway.

• #42 Uterine Fibroids: Pathogenesis and Interactions with Endometrium and Endomyometrial Junction

  https://pmc.ncbi.nlm.nih.gov/articles/PMC3791844/

  Another interesting theory underlines that the pathogenesis might be similar to a response to injury; ischemic damage could be linked to release of increased vasoconstrictive substances at the time of the menses. […] Historically, uterine leiomyomata have not been considered a genetic disease. However much recent clinical evidence indicates that at least some myomata have a genetic etiology. […] Recent studies described that 70% of fibroids contained a series of mutations in a transcriptional regulator complex subunit 12 (MED12). […] Research for the pathogenesis of fibroids and abnormal extracellular matrix (ECM) led to the analysis of a growth factor with profibrotic activity, transforming growth factor (TGF-). […] Epigenetic changes have also been implicated in leiomyoma formation.

• #43 Update on the Role and Regulatory Mechanism of Extracellular Matrix in the Pathogenesis of Uterine Fibroids

  https://www.mdpi.com/1422-0067/24/6/5778

  Numerous studies demonstrated that TGF-β signaling plays an important role in the pathogenesis of UFs. […] Abnormal ECM accumulation and deposition have been shown to be associated with the activation of TGF-β signaling in UFs. […] The ECM acts as a reservoir of profibrotic growth factors and enhances their activity by increasing their stability and prolonging signaling duration. […] The significant variations in the quantity and distribution of the ECM also create variation in the degree of UF tissue stiffness from soft to firm to solid to hard, with a major impact on the gene expression and biology of these tumor lesions. […] Pharmacological drugs can suppress the UF phenotype by inhibiting ECM production via multiple mechanisms, including epigenetics. […] The deep mechanistic and functional investigation will help us better understand the regulatory mechanism of ECM-secreted cell types, cell–cell interaction, and environmental impacts on the risk and development of UFs.

• #44

  https://www.fibroids.net/pubfart4.html

  Recent progress in defining the molecular mechanisms of angiogenesis in the uterus lends support to this theory by demonstrating local dysregulation of vasoactive growth factors or growth factor receptors in leiomyomas or leiomyomatous myometrium. Thus, the molecular mechanisms underlying the process of leiomyoma-related menorrhagia are delineated. […] Current evidence suggests that it is not physical compression but the local action of vasoactive growth factors which have altered synthesis, expression or sequestration in leiomyomas, that account for these vascular abnormalities. […] This paradigm of dysregulation of growth factor function that results in disruption of normal vascular function appears relevant for non-uterine bleeding disorders. […] Growth factors or their receptors that are differentially regulated in the leiomyomas or the endometrium of leiomyomatous uteri are potential mediators of leiomyoma-related complications. These differentially regulated factors, which are known to act on vascular tissue by increasing proliferation or changing vessel caliber, are potential causes of leiomyoma-related menorrhagia. […] Thus, TGF-b3 may contribute to the enhanced growth of leiomyomas by increasing cell proliferation as well as potentially increasing ECM production. Alternatively, the decreased levels of TGF-b type II receptor may allow for decreased growth inhibition by TGF-b1.

• #45

  https://www.fibroids.net/pubfart4.html

  Recent progress in defining the molecular mechanisms of angiogenesis in the uterus lends support to this theory by demonstrating local dysregulation of vasoactive growth factors or growth factor receptors in leiomyomas or leiomyomatous myometrium. Thus, the molecular mechanisms underlying the process of leiomyoma-related menorrhagia are delineated. […] Current evidence suggests that it is not physical compression but the local action of vasoactive growth factors which have altered synthesis, expression or sequestration in leiomyomas, that account for these vascular abnormalities. […] This paradigm of dysregulation of growth factor function that results in disruption of normal vascular function appears relevant for non-uterine bleeding disorders. […] Growth factors or their receptors that are differentially regulated in the leiomyomas or the endometrium of leiomyomatous uteri are potential mediators of leiomyoma-related complications. These differentially regulated factors, which are known to act on vascular tissue by increasing proliferation or changing vessel caliber, are potential causes of leiomyoma-related menorrhagia. […] Thus, TGF-b3 may contribute to the enhanced growth of leiomyomas by increasing cell proliferation as well as potentially increasing ECM production. Alternatively, the decreased levels of TGF-b type II receptor may allow for decreased growth inhibition by TGF-b1.

• #46 Pathogenesis, Classification, Histopathology, and Symptomatology of Fibroids | Obgyn Key

  https://obgynkey.com/pathogenesis-classification-histopathology-and-symptomatology-of-fibroids/

  Uterine fibroid cells typically show a high expression of cell-cycle regulator and anti-apoptotic proteins. […] This can trigger tumor growth and make cells resistant to apoptosis. […] Somatic mutations involving the gene encoding the mediator complex subunit 12 (MED12) and the gene encoding the high-mobility group AT-hook 2 (HMGA2) are known to be associated to fibroids. […] The role of the wingless-type (Wnt) pathway in supporting tumor initiation of fibroids is well demonstrated. […] Other studies have demonstrated a central role for the phosphoinositide 3-kinaseprotein kinase B/AKT (PI3K/AKT) pathway leading to the activation of mammalian target of rapamycin (mTOR) in the pathogenesis of fibroids.

• #47

  https://www-.grantome.com/grant/NIH/R01-HD076450-03

  Uterine fibroids (leiomyomas) are benign smooth muscle cell (SMC) tumors of the myometrium. […] Dysregulated PI3K/AKT pathway leading to the activation of mTOR has been suggested to play an essential role in the pathogenesis of leiomyomas. Our preliminary data suggest that GPR10, a GPCR normally silenced in the periphery by the tumor suppressor REST/ NRSF, is near ubiquitously over-expressed human leiomyomas. Further, REST protein is dramatically reduced in leiomyomas. […] We hypothesize that the loss of REST leads to GPR10 expression in leiomyomas and this aberrant gene expression functionally promotes cell proliferation contributing to the pathogenesis of uterine fibroids. The current project will establish the functional role that the loss of REST has on the pathogenesis of uterine fibroids using in vitro methods and novel in vivo genetic models.

• #48 Vascular biology of uterine fibroids: connecting fibroids and vascular disorders in: Reproduction Volume 162 Issue 2 (2021)

  https://rep.bioscientifica.com/view/journals/rep/162/2/REP-21-0087.xml

  In fact, inhibition of this pathway by gonadotropin receptor hormone (GnRH) therapy triggers fibroid cell apoptosis and is one modality of treatment for symptomatic fibroids. […] Given new developments in fibroid research, we lay out accumulating evidence in this article that fibroids may, at least in some circumstances, be part of a vascular disease process. […] Uterine remodeling during pregnancy is now thought to also have a vasculogenic component. […] While vasculogenesis in uterine fibroids has yet to be definitively identified, these tumors have shown the capability to secrete CXCL12, a chemokine that recruits BMDCs, perhaps facilitating fibroid growth through engrafting stem cells into the tumor. […] Dysregulated angiogenesis has been reportedly noted in a wide array of uterine pathologies, including placenta accreta spectrum, abnormal uterine bleeding, as well as the focus of this review, uterine fibroids.

• #49 Update on the Role and Regulatory Mechanism of Extracellular Matrix in the Pathogenesis of Uterine Fibroids

  https://www.mdpi.com/1422-0067/24/6/5778

  Uterine fibroids (UFs), also known as leiomyomas, are benign tumors of the myometrium affecting over 70% of women worldwide, particularly women of color. […] So far, the molecular mechanisms underlying the pathogenesis of UFs are still quite limited. […] Excessive ECM accumulation and aberrant remodeling are crucial for fibrotic diseases and excessive ECM deposition is the central characteristics of UFs. […] Several risk factors have been shown to impact UF pathogenesis and are associated with a higher probability of UF formation and development. […] These risk factors affect several key pathways, including inflammation, DNA damage repair pathway, β-catenin pathway, and genetic instability, among others, leading to the pathogenesis of UFs. […] UFs are characterized by the excessive deposition of ECM proteins, such as collagens, fibronectin, and proteoglycans, representing fibrosis.

• #50 Update on the Role and Regulatory Mechanism of Extracellular Matrix in the Pathogenesis of Uterine Fibroids

  https://www.mdpi.com/1422-0067/24/6/5778

  Uterine fibroids (UFs), also known as leiomyomas, are benign tumors of the myometrium affecting over 70% of women worldwide, particularly women of color. […] So far, the molecular mechanisms underlying the pathogenesis of UFs are still quite limited. […] Excessive ECM accumulation and aberrant remodeling are crucial for fibrotic diseases and excessive ECM deposition is the central characteristics of UFs. […] Several risk factors have been shown to impact UF pathogenesis and are associated with a higher probability of UF formation and development. […] These risk factors affect several key pathways, including inflammation, DNA damage repair pathway, β-catenin pathway, and genetic instability, among others, leading to the pathogenesis of UFs. […] UFs are characterized by the excessive deposition of ECM proteins, such as collagens, fibronectin, and proteoglycans, representing fibrosis.

• #51 Uterine fibroid – Wikipedia

  https://en.wikipedia.org/wiki/Uterine_fibroid

  Expansion of uterine fibroids occurs by a slow rate of cell proliferation combined with the production of copious amounts of extracellular matrix. […] A small population of the cells in a uterine fibroid have properties of stem cells or progenitor cells, and contribute significantly to ovarian steroid-dependent growth of fibroids. These stem-progenitor cells are deficient in estrogen receptor and progesterone receptor and instead rely on substantially higher levels of these receptors in surrounding differentiated cells to mediate estrogen and progesterone actions via paracrine signaling.

• #52 Update on the Role and Regulatory Mechanism of Extracellular Matrix in the Pathogenesis of Uterine Fibroids

  https://www.mdpi.com/1422-0067/24/6/5778

  Numerous studies demonstrated that TGF-β signaling plays an important role in the pathogenesis of UFs. […] Abnormal ECM accumulation and deposition have been shown to be associated with the activation of TGF-β signaling in UFs. […] The ECM acts as a reservoir of profibrotic growth factors and enhances their activity by increasing their stability and prolonging signaling duration. […] The significant variations in the quantity and distribution of the ECM also create variation in the degree of UF tissue stiffness from soft to firm to solid to hard, with a major impact on the gene expression and biology of these tumor lesions. […] Pharmacological drugs can suppress the UF phenotype by inhibiting ECM production via multiple mechanisms, including epigenetics. […] The deep mechanistic and functional investigation will help us better understand the regulatory mechanism of ECM-secreted cell types, cell–cell interaction, and environmental impacts on the risk and development of UFs.

• #53 RISING STARS: Role of MED12 mutation in the pathogenesis of uterine fibroids in: Journal of Molecular Endocrinology Volume 71 Issue 4 (2023)

  https://jme.bioscientifica.com/view/journals/jme/71/4/JME-23-0039.xml

  Uterine fibroids (UFs) are benign tumors arising from the uterus, characterized by accumulation of abundant extracellular matrix (ECM) and sex steroid-dependent growth. […] Among the driver gene mutations identified in UFs, mutations in MED12, a component of the cyclin-dependent kinase (CDK) Mediator module, are the most common and observed in 50-80% of UFs. […] MED12 mutation-positive UFs (MED12-UFs) often develop multiple rather than solitary and have distinct gene expression profiles, DNA methylomes, transcriptomes, and proteomes. […] Gene expressions related to ECM organization and collagen-rich ECM components are upregulated, and impaired Mediator kinase activity and dysregulation of Wnt/-catenin signaling are identified in MED12-UFs. […] Understanding of characteristics of MED12-UFs and functions of MED12 mutations for UF tumorigenesis may elucidate the pathophysiology of UFs, leading to the development of new therapeutic options in women with symptomatic UFs.

• #54 Update on the Role and Regulatory Mechanism of Extracellular Matrix in the Pathogenesis of Uterine Fibroids

  https://www.mdpi.com/1422-0067/24/6/5778

  Numerous studies demonstrated that TGF-β signaling plays an important role in the pathogenesis of UFs. […] Abnormal ECM accumulation and deposition have been shown to be associated with the activation of TGF-β signaling in UFs. […] The ECM acts as a reservoir of profibrotic growth factors and enhances their activity by increasing their stability and prolonging signaling duration. […] The significant variations in the quantity and distribution of the ECM also create variation in the degree of UF tissue stiffness from soft to firm to solid to hard, with a major impact on the gene expression and biology of these tumor lesions. […] Pharmacological drugs can suppress the UF phenotype by inhibiting ECM production via multiple mechanisms, including epigenetics. […] The deep mechanistic and functional investigation will help us better understand the regulatory mechanism of ECM-secreted cell types, cell–cell interaction, and environmental impacts on the risk and development of UFs.

• #55 Uterine Fibroids: Pathogenesis and Interactions with Endometrium and Endomyometrial Junction

  https://pmc.ncbi.nlm.nih.gov/articles/PMC3791844/

  Uterine leiomyoma growth is strictly related to estrogens and their receptors. […] Leiomyoma growth is influenced by progesterone interaction with some growth factors; it upregulates the EGF (mitogenic) and transforming growth factor- (TGF-)3 (bimodal action). […] Several growth factors, such as vascular endothelial growth factor (VEGF), EGF, heparin binding epidermal growth factor (HB-EGF), PDGF, IGF, TGF-, TGF-, acidic fibroblast growth factor (aFGF), and basic fibroblast growth factor (bFGF), and their respective receptors have been demonstrated to play a role in leiomyoma growth. […] Many cytokines, including tumor necrosis factor-, erythropoietin, interleukin- (IL-)1, and IL-6, have been implicated in development of uterine leiomyoma. […] Extracellular disorganized matrix is a peculiar characteristic of fibroid growth, mainly consisting of collagen subtypes, fibronectin, and proteoglycans. […] The etiopathology of uterine fibroid remains unclear, multifactorial, and enigmatic. […] Abnormal ECM expression, increased growth factors, cytokines and chemokines concentrations, and an extracellular disorganized matrix have been implicated in development and growth of uterine leiomyomas.

• #56 Progesterone Signaling and Uterine Fibroid Pathogenesis; Molecular Mechanisms and Potential Therapeutics

  https://www.mdpi.com/2073-4409/12/8/1117

  Progesterone has been shown to suppress apoptosis in fibroid cells, which may contribute more to the growth of UFs via B-cell lymphoma- (Bcl-) 2 protein expression induction than myometrium. […] Progesterone has been shown to modulate the production of cytokines such as TNF-α and IL-6. […] The findings of Liu et al. suggested that DNA methylation and MED12 mutation together constitute a complex regulatory network that affects progesterone/PR-mediated RANKL gene expression, with an essential role in activating stem cell proliferation and fibroid tumor development. […] Since the formation of new blood vessels is vital for the delivery of nutrients and oxygen to the growing tumors, progesterone may promote angiogenesis through the upregulation of VEGF which stimulates the growth of blood vessels.

• #57 Uterine Fibroids: Pathogenesis and Interactions with Endometrium and Endomyometrial Junction

  https://pmc.ncbi.nlm.nih.gov/articles/PMC3791844/

  Uterine leiomyoma growth is strictly related to estrogens and their receptors. […] Leiomyoma growth is influenced by progesterone interaction with some growth factors; it upregulates the EGF (mitogenic) and transforming growth factor- (TGF-)3 (bimodal action). […] Several growth factors, such as vascular endothelial growth factor (VEGF), EGF, heparin binding epidermal growth factor (HB-EGF), PDGF, IGF, TGF-, TGF-, acidic fibroblast growth factor (aFGF), and basic fibroblast growth factor (bFGF), and their respective receptors have been demonstrated to play a role in leiomyoma growth. […] Many cytokines, including tumor necrosis factor-, erythropoietin, interleukin- (IL-)1, and IL-6, have been implicated in development of uterine leiomyoma. […] Extracellular disorganized matrix is a peculiar characteristic of fibroid growth, mainly consisting of collagen subtypes, fibronectin, and proteoglycans. […] The etiopathology of uterine fibroid remains unclear, multifactorial, and enigmatic. […] Abnormal ECM expression, increased growth factors, cytokines and chemokines concentrations, and an extracellular disorganized matrix have been implicated in development and growth of uterine leiomyomas.

• #58 Uterine Fibroids: Pathogenesis and Interactions with Endometrium and Endomyometrial Junction

  https://pmc.ncbi.nlm.nih.gov/articles/PMC3791844/

  Uterine leiomyoma growth is strictly related to estrogens and their receptors. […] Leiomyoma growth is influenced by progesterone interaction with some growth factors; it upregulates the EGF (mitogenic) and transforming growth factor- (TGF-)3 (bimodal action). […] Several growth factors, such as vascular endothelial growth factor (VEGF), EGF, heparin binding epidermal growth factor (HB-EGF), PDGF, IGF, TGF-, TGF-, acidic fibroblast growth factor (aFGF), and basic fibroblast growth factor (bFGF), and their respective receptors have been demonstrated to play a role in leiomyoma growth. […] Many cytokines, including tumor necrosis factor-, erythropoietin, interleukin- (IL-)1, and IL-6, have been implicated in development of uterine leiomyoma. […] Extracellular disorganized matrix is a peculiar characteristic of fibroid growth, mainly consisting of collagen subtypes, fibronectin, and proteoglycans. […] The etiopathology of uterine fibroid remains unclear, multifactorial, and enigmatic. […] Abnormal ECM expression, increased growth factors, cytokines and chemokines concentrations, and an extracellular disorganized matrix have been implicated in development and growth of uterine leiomyomas.

• #59 Progesterone Signaling and Uterine Fibroid Pathogenesis; Molecular Mechanisms and Potential Therapeutics

  https://www.mdpi.com/2073-4409/12/8/1117

  Progesterone has been shown to suppress apoptosis in fibroid cells, which may contribute more to the growth of UFs via B-cell lymphoma- (Bcl-) 2 protein expression induction than myometrium. […] Progesterone has been shown to modulate the production of cytokines such as TNF-α and IL-6. […] The findings of Liu et al. suggested that DNA methylation and MED12 mutation together constitute a complex regulatory network that affects progesterone/PR-mediated RANKL gene expression, with an essential role in activating stem cell proliferation and fibroid tumor development. […] Since the formation of new blood vessels is vital for the delivery of nutrients and oxygen to the growing tumors, progesterone may promote angiogenesis through the upregulation of VEGF which stimulates the growth of blood vessels.

• #60 Vascular biology of uterine fibroids: connecting fibroids and vascular disorders in: Reproduction Volume 162 Issue 2 (2021)

  https://rep.bioscientifica.com/view/journals/rep/162/2/REP-21-0087.xml

  Fibroids are benign tumors caused by the proliferation of myometrial smooth muscle cells in the uterus that can lead to symptoms such as abdominal pain, constipation, urinary retention, and infertility. […] While traditionally thought of as a disease process intrinsic to the uterus, accumulating evidence suggests that fibroid growth may be linked with the systemic vasculature system, although cell-intrinsic factors are certainly of principal importance in their inception. […] Fibroids are associated with essential hypertension and preeclampsia, as well as atherosclerosis, for reasons that are becoming increasingly elucidated. […] Factors such as the renin-angiotensinaldosterone system, estrogen, and endothelial dysfunction all likely play a role in fibroid pathogenesis. […] In this review, we lay out a framework for reconceptualizing fibroids as a systemic vascular disorder, and discuss how pharmaceutical agents and other interventions targeting the vasculature may aid in the novel treatment of fibroids.

• #61 Vascular biology of uterine fibroids: connecting fibroids and vascular disorders in: Reproduction Volume 162 Issue 2 (2021)

  https://rep.bioscientifica.com/view/journals/rep/162/2/REP-21-0087.xml

  Uterine fibroids have a well-vascularized capsule yet a hypovascular core, a unique demarcation that has led the scientists to propose the presence of an inherent angiogenic defect. […] The association between uterine fibroids and hypertension has been extensively addressed in the literature. […] A prospective study has examined the relation between diastolic blood pressure and the incidence of clinically detected uterine fibroids and detected a 10 and 8% rise in fibroid risk for each 10 mmHg increase in diastolic blood pressure among users and nonusers of antihypertensives, respectively. […] Elevated blood pressure also induces proinflammatory milieus and upregulates ECM synthesis, in part through the action of TGF-, which has been seen to activate fibroblasts in rats induced to have hypertension.

• #62

  https://www.archivesofmedicalscience.com/Identification-of-PDGFR-cells-in-uterine-fibroids-link-between-angiogenesis-and-uterine,110052,0,2.html

  We observed a decrease of vascularization in the foci of leiomyoma, accompanied by increasing expression of VEGF receptor-1 (sFlt-1). […] Uterine telocytes are sensitive to angiogenic factors (PDGF and VEGF) and ischemia; they declined and even disappeared during fibrosis, observed in close vicinity to blood vessels. They might play a role in the angiogenic response, universal for the human body. […] We hypothesize that in-depth observation of TCs in the human uterus brings additional value to reproductive medicine.

• #63 Vascular biology of uterine fibroids: connecting fibroids and vascular disorders in: Reproduction Volume 162 Issue 2 (2021)

  https://rep.bioscientifica.com/view/journals/rep/162/2/REP-21-0087.xml

  In fact, inhibition of this pathway by gonadotropin receptor hormone (GnRH) therapy triggers fibroid cell apoptosis and is one modality of treatment for symptomatic fibroids. […] Given new developments in fibroid research, we lay out accumulating evidence in this article that fibroids may, at least in some circumstances, be part of a vascular disease process. […] Uterine remodeling during pregnancy is now thought to also have a vasculogenic component. […] While vasculogenesis in uterine fibroids has yet to be definitively identified, these tumors have shown the capability to secrete CXCL12, a chemokine that recruits BMDCs, perhaps facilitating fibroid growth through engrafting stem cells into the tumor. […] Dysregulated angiogenesis has been reportedly noted in a wide array of uterine pathologies, including placenta accreta spectrum, abnormal uterine bleeding, as well as the focus of this review, uterine fibroids.

• #64 Vascular biology of uterine fibroids: connecting fibroids and vascular disorders in: Reproduction Volume 162 Issue 2 (2021)

  https://rep.bioscientifica.com/view/journals/rep/162/2/REP-21-0087.xml

  The consistent evidence of the correlation between hypertension and uterine fibroids raises the prospect, once again, of vascular involvement in fibroid pathobiology. […] An accumulating body of evidence has supported the notion that uterine fibroids and atherosclerosis bear pathophysiological resemblance. […] This hypothesis is reinforced by several observations: (1) both atherosclerosis and uterine fibroids represent a pathological proliferative lesion of smooth muscle cells; (2) similar to fibroids, atheromatous plaques may have a monoclonal origin; and (3) both lesions can eventually fibrose and calcify. […] Elevated ET-1, in turn, drives systemic vasoconstriction, vascular dysfunction, and elevated mean arterial pressure, all characteristics of preeclampsia. […] The fact that fibroids are also associated with elevated ET-1 levels and systemic hypertension suggests a possible unifying pathogenic link between these two disease entities that can be traced to abnormal uterine vascularity.

• #65 Vascular biology of uterine fibroids: connecting fibroids and vascular disorders in: Reproduction Volume 162 Issue 2 (2021)

  https://rep.bioscientifica.com/view/journals/rep/162/2/REP-21-0087.xml

  The consistent evidence of the correlation between hypertension and uterine fibroids raises the prospect, once again, of vascular involvement in fibroid pathobiology. […] An accumulating body of evidence has supported the notion that uterine fibroids and atherosclerosis bear pathophysiological resemblance. […] This hypothesis is reinforced by several observations: (1) both atherosclerosis and uterine fibroids represent a pathological proliferative lesion of smooth muscle cells; (2) similar to fibroids, atheromatous plaques may have a monoclonal origin; and (3) both lesions can eventually fibrose and calcify. […] Elevated ET-1, in turn, drives systemic vasoconstriction, vascular dysfunction, and elevated mean arterial pressure, all characteristics of preeclampsia. […] The fact that fibroids are also associated with elevated ET-1 levels and systemic hypertension suggests a possible unifying pathogenic link between these two disease entities that can be traced to abnormal uterine vascularity.

• #66 Uterine fibroid – Wikipedia

  https://en.wikipedia.org/wiki/Uterine_fibroid

  Expansion of uterine fibroids occurs by a slow rate of cell proliferation combined with the production of copious amounts of extracellular matrix. […] A small population of the cells in a uterine fibroid have properties of stem cells or progenitor cells, and contribute significantly to ovarian steroid-dependent growth of fibroids. These stem-progenitor cells are deficient in estrogen receptor and progesterone receptor and instead rely on substantially higher levels of these receptors in surrounding differentiated cells to mediate estrogen and progesterone actions via paracrine signaling.

• #67 Uterine fibroid – Wikipedia

  https://en.wikipedia.org/wiki/Uterine_fibroid

  Expansion of uterine fibroids occurs by a slow rate of cell proliferation combined with the production of copious amounts of extracellular matrix. […] A small population of the cells in a uterine fibroid have properties of stem cells or progenitor cells, and contribute significantly to ovarian steroid-dependent growth of fibroids. These stem-progenitor cells are deficient in estrogen receptor and progesterone receptor and instead rely on substantially higher levels of these receptors in surrounding differentiated cells to mediate estrogen and progesterone actions via paracrine signaling.

• #68 Pathogenesis, Classification, Histopathology, and Symptomatology of Fibroids | Obgyn Key

  https://obgynkey.com/pathogenesis-classification-histopathology-and-symptomatology-of-fibroids/

  Uterine fibroids are thought to be monoclonal uterine mass that occurs via clonal expansion from a single mutated myometrial smooth muscle stem cell. […] A current model suggests that a distinct stem/reservoir cell-enriched population, designated as the leiomyoma-derived side population (LMSP), is responsible to sustain proliferation and tumor growth. […] Hormones have been considered as the major promoter of fibroid growth. In addition, several pathogenic factors such as genetics, microRNA, growth factors, cytokines, and chemokines have a role in the fibroid development and growth. […] The fibroid mechanical properties are another key feature of these benign tumors that may contribute to their growth. Fibroids are in fact stiff tumors characterized by an excessive deposition of disordered extracellular matrix (ECM) components, particularly collagen I, III, and IV, proteoglycans, and fibronectin.

• #69 Progesterone Signaling and Uterine Fibroid Pathogenesis; Molecular Mechanisms and Potential Therapeutics

  https://www.mdpi.com/2073-4409/12/8/1117

  Uterine fibroids (UFs) are the most important benign neoplastic threat to women’s health worldwide, with a prevalence of up to 80% in premenopausal women, and can cause heavy menstrual bleeding, pain, and infertility. Progesterone signaling plays a crucial role in the development and growth of UFs. Progesterone promotes the proliferation of UF cells by activating several signaling pathways genetically and epigenetically. […] The UF pathogenesis model invokes the genetic transformation of a single myometrial stem cell (MMSC) into a tumor-initiating cell (UFSC) that seeds and sustains clonal tumor growth. This is characterized by an increase in cell size and number as well as abundant ECM production, under the influence of endocrine, autocrine, and paracrine growth factors and hormone receptor signaling.

• #70 Progesterone Signaling and Uterine Fibroid Pathogenesis; Molecular Mechanisms and Potential Therapeutics

  https://www.mdpi.com/2073-4409/12/8/1117

  Uterine fibroids (UFs) are the most important benign neoplastic threat to women’s health worldwide, with a prevalence of up to 80% in premenopausal women, and can cause heavy menstrual bleeding, pain, and infertility. Progesterone signaling plays a crucial role in the development and growth of UFs. Progesterone promotes the proliferation of UF cells by activating several signaling pathways genetically and epigenetically. […] The UF pathogenesis model invokes the genetic transformation of a single myometrial stem cell (MMSC) into a tumor-initiating cell (UFSC) that seeds and sustains clonal tumor growth. This is characterized by an increase in cell size and number as well as abundant ECM production, under the influence of endocrine, autocrine, and paracrine growth factors and hormone receptor signaling.

• #71 Uterine Fibroids: Pathogenesis and Interactions with Endometrium and Endomyometrial Junction

  https://pmc.ncbi.nlm.nih.gov/articles/PMC3791844/

  Another interesting theory underlines that the pathogenesis might be similar to a response to injury; ischemic damage could be linked to release of increased vasoconstrictive substances at the time of the menses. […] Historically, uterine leiomyomata have not been considered a genetic disease. However much recent clinical evidence indicates that at least some myomata have a genetic etiology. […] Recent studies described that 70% of fibroids contained a series of mutations in a transcriptional regulator complex subunit 12 (MED12). […] Research for the pathogenesis of fibroids and abnormal extracellular matrix (ECM) led to the analysis of a growth factor with profibrotic activity, transforming growth factor (TGF-). […] Epigenetic changes have also been implicated in leiomyoma formation.

• #72 Uterine fibroids: a look at the problem | Karamyan | Medical Herald of the South of Russia

  https://www.medicalherald.ru/jour/article/view/1561?locale=en_US

  Despite scientific progress, there is currently no single opinion about the cause of the occurrence and recurrence of uterine fibroids, but due to the high level of molecular medicine, progress is being made in the hormonal and molecular genetic mechanisms of initiation, formation and growth of the fibroids. […] The epigenetic processes of regulation and pathogenesis of the growth of leiomyomas in reproductive age have not been fully studied and substantiated. […] Abnormal myometrial and fibroid stem cells show an increased response to estrogen and progesterone exposure, stimulating processes such as cell proliferation, inhibition of apoptosis, and extracellular matrix (ECM) formation. […] A number of tumor suppressor genes are abnormally hypermethylated in the LM when compared to normal myometrium, genes that form and regulate collagen, and a subset of estrogen receptor genes.

• #73 Progesterone Signaling and Uterine Fibroid Pathogenesis; Molecular Mechanisms and Potential Therapeutics

  https://www.mdpi.com/2073-4409/12/8/1117

  Progesterone has been shown to suppress apoptosis in fibroid cells, which may contribute more to the growth of UFs via B-cell lymphoma- (Bcl-) 2 protein expression induction than myometrium. […] Progesterone has been shown to modulate the production of cytokines such as TNF-α and IL-6. […] The findings of Liu et al. suggested that DNA methylation and MED12 mutation together constitute a complex regulatory network that affects progesterone/PR-mediated RANKL gene expression, with an essential role in activating stem cell proliferation and fibroid tumor development. […] Since the formation of new blood vessels is vital for the delivery of nutrients and oxygen to the growing tumors, progesterone may promote angiogenesis through the upregulation of VEGF which stimulates the growth of blood vessels.

• #74 Uterine Fibroids: Pathogenesis and Interactions with Endometrium and Endomyometrial Junction

  https://pmc.ncbi.nlm.nih.gov/articles/PMC3791844/

  Another interesting theory underlines that the pathogenesis might be similar to a response to injury; ischemic damage could be linked to release of increased vasoconstrictive substances at the time of the menses. […] Historically, uterine leiomyomata have not been considered a genetic disease. However much recent clinical evidence indicates that at least some myomata have a genetic etiology. […] Recent studies described that 70% of fibroids contained a series of mutations in a transcriptional regulator complex subunit 12 (MED12). […] Research for the pathogenesis of fibroids and abnormal extracellular matrix (ECM) led to the analysis of a growth factor with profibrotic activity, transforming growth factor (TGF-). […] Epigenetic changes have also been implicated in leiomyoma formation.

• #75 A Rare Case of Large Uterine Myoma in an Antenatal Women with Situs Inversus: A Case Report

  https://clinmedjournals.org/articles/ogcr/obstetrics-and-gynaecology-cases-reviews-ogcr-6-144.php

  Leiomyomas or fibroids are the most common benign tumor of uterus and it often increases in size during pregnancy. […] The exact etiology of uterine fibroids is still unclear with many theories of its origin. Various factors like genetic predisposition, steroid hormones, environmental factors, etc. play an important role in the fibrotic processes and angiogenesis, ultimately leading to formation and growth of uterine fibroids. […] The exact pathogenesis of these smooth muscle tumours is not clear, but the two main ovarian steroidal hormones; oestradiol and progesterone play a significant role in its growth. The growth promoting effects of these hormones is mainly through local production of specific growth factors which causes augmentation of mitotic rate. […] Another theory that explains the pathogenesis is response to injury, especially during menstrual cycle in which ischemic damage leads to release of various vasoconstrictive substances, which causes smooth muscle cells of the myometrium to react and synthesis extracellular fibrous matrix. […] A variety of factors such as epigenetic or genetic mechanism, disorganization of extracellular matrix, growth factors have shown interaction with pathogenesis of growing fibroid.

• #76

  https://www.trialx.com/clinical-trials/listings/265932/role-of-senescent-cells-in-uterine-fibroid-pathogenesis-soul-study/

  The investigators are evaluating the role of senescent cells in uterine fibroids. […] Using new cutting-edge computational methods, the investigators have found that small groups of senescent cells in fibroids work in concert with immune cells to produce soluble factors in fibroid tissues to create a feed-forward loop leading to fibrosis. […] This project seeks to unravel key cell-cell communication networks involving senescent and immune cells in fibroids to develop new treatments for uterine fibroids.

• #77

  https://www.trialx.com/clinical-trials/listings/265932/role-of-senescent-cells-in-uterine-fibroid-pathogenesis-soul-study/

  The investigators are evaluating the role of senescent cells in uterine fibroids. […] Using new cutting-edge computational methods, the investigators have found that small groups of senescent cells in fibroids work in concert with immune cells to produce soluble factors in fibroid tissues to create a feed-forward loop leading to fibrosis. […] This project seeks to unravel key cell-cell communication networks involving senescent and immune cells in fibroids to develop new treatments for uterine fibroids.

• #78 Uterine Fibroids Initiation and Pathogenesis | Endocrine Society

  https://www.endocrine.org/journals/endocrine-reviews/uterine-fibroids-initiation-and-pathogenesis

  Uterine fibroids are benign monoclonal neoplasms of the myometrium, representing the most common tumors in women worldwide. […] To date, no long-term or noninvasive treatment option exists for hormone-dependent uterine fibroids, due to the limited knowledge about the molecular mechanisms underlying the initiation and development of uterine fibroids. […] This paper comprehensively summarizes the recent research advances on uterine fibroids, focusing on risk factors, development origin, pathogenetic mechanisms, and treatment options. […] Deeper mechanistic insights into tumor etiology and the complexity of uterine fibroids can contribute to the progress of newer targeted therapies.

• #79 Progesterone Signaling and Uterine Fibroid Pathogenesis; Molecular Mechanisms and Potential Therapeutics

  https://www.mdpi.com/2073-4409/12/8/1117

  Although the leading causes of fibroids are unknown, accumulating epidemiological, clinical, and experimental evidence supports the pivotal role of ovarian steroid hormones in the growth and pathogenesis of UFs. […] Importantly, progesterone action is complex and involves interaction with receptors, transcription factors, kinase proteins, growth factors, and numerous autocrine and paracrine factors. […] The promising results of utilizing selective progesterone receptor modulators (SPRM) in controlling UF-associated symptoms such as bleeding as well as tumor shrinkage, further supports the role progesterone plays in UF pathogenesis. […] Disrupted progesterone signaling is causally linked to many reproductive diseases that result in subfertility or infertility, including UF. […] Studies demonstrated that progesterone signaling promotes the growth and proliferation of fibroid cells through increasing proliferating cell nuclear antigen (PCNA) expression, which increases both the number of fibroid cells and the size of fibroid tumors.

• #80 Pathophysiology of uterine fibroids

  https://www.contemporaryobgyn.net/view/pathophysiology-of-uterine-fibroids

  A better understanding of the pathophysiology of uterine fibroids (UFs) will enable healthcare providers to deliver high-quality informed care to their patients, according to Ayman Al-Hendy, MD, PhD, a professor of ob/gyn at Pritzker School of Medicine, University of Chicago. […] Pathophysiology also enables providers to understand the mechanism of action of the various treatment tools, so they can tailor and match an appropriate treatment to a specific patient, Al-Hendy told Contemporary OB/GYN. […] The key pathways are estrogen, progesterone, DNA damage, transforming growth factor beta, growth factors, the canonical Wnt pathway and extracellular matrix (ECM) remodeling. […] But we have limited safe treatment options for fibroid patients who want to preserve their fertility potential, Al-Hendy said. We also do not understand how fibroids cause heavy menstrual bleeding or infertility. […] Investigating genetic correlations and shared loci sheds light on potential causal relationships between reproductive traits and uterine leiomyomata, offering insights into their complex interplay and urging further mechanistic exploration.

• #81 Why do fibroids in the uterus cause severe bleeding?

  https://chennaigynecologist.com/why-do-fibroids-in-the-uterus-cause-severe-bleeding/

  Angiogenesis in fibroids can cause severe bleeding – There is no other tissue in the human body that undergoes angiogenesis to the degree and frequency as the endometrium. […] Pseudocapsule in fibroids could explain severe bleeding – The fibroid mass is poorly vascularised but it can be surrounded by a pseudocapsule which is a highly vascularised tissue that develops only in intramural fibroids. […] Venous lakes in fibroids can be responsible for increased bleeding – Severe bleeding connected to uterine fibroids suggests physiological formation of venous lakes which are large sinusoidal structures within the uterine vasculature from arteriovenous anastomoses. […] Aberrant architecture of fibroid can cause severe bleeding – The vasculature developing around uterine fibroids could show structural defects that could be highly irregular, with high tortuosity, shunting of vessels and non-patent ends.

• #82 Why do fibroids in the uterus cause severe bleeding?

  https://chennaigynecologist.com/why-do-fibroids-in-the-uterus-cause-severe-bleeding/

  Angiogenesis in fibroids can cause severe bleeding – There is no other tissue in the human body that undergoes angiogenesis to the degree and frequency as the endometrium. […] Pseudocapsule in fibroids could explain severe bleeding – The fibroid mass is poorly vascularised but it can be surrounded by a pseudocapsule which is a highly vascularised tissue that develops only in intramural fibroids. […] Venous lakes in fibroids can be responsible for increased bleeding – Severe bleeding connected to uterine fibroids suggests physiological formation of venous lakes which are large sinusoidal structures within the uterine vasculature from arteriovenous anastomoses. […] Aberrant architecture of fibroid can cause severe bleeding – The vasculature developing around uterine fibroids could show structural defects that could be highly irregular, with high tortuosity, shunting of vessels and non-patent ends.

• #83 A COMPREHENSIVE REVIEW OF UTERINE FIBROIDS: PATHOGENESIS, DIAGNOSIS, TREATMENT, AND FUTURE PERSPECTIVES | Journal of Population Therapeutics and Clinical Pharmacology

  https://www.jptcp.com/index.php/jptcp/article/view/3385

  Fibroid, myoma, and leiomyoma are interchangeable terms used to describe the most common gynecological tumors, which are benign neoplasms originating in the smooth muscles of the uterus. […] Age and race are the primary risk factors for uterine fibroids, with African American women experiencing higher incidence rates compared to Caucasian women. A family history of uterine fibroids also increases the risk of developing them. […] Lifestyle factors such as obesity, dietary choices, sedentary living, and smoking have been linked to fibroid occurrence, possibly due to their influence on estrogen production. […] Stress may also be a contributing risk factor for fibroids, as it is associated with a higher body mass index. […] A diet rich in red meat has been connected to a 70% increased risk of fibroids. […] It’s worth noting that large fibroids can impact the uterine cavity’s configuration, potentially affecting embryo implantation and increasing the risk of miscarriage.

• #84 The meaning and management of uterine fibroids in pregnancy: a narrative review of the literature – Gemici – Gynecology and Pelvic Medicine

  https://gpm.amegroups.org/article/view/9358/html

  Uterine fibroids are the clonal formation of the mesenchimal cell line that turns into tumor formation in either location (submucous, intramural, subserous and serous) at the uterus. […] The relationship between uterine fibroids and adverse pregnancy outcome is not clearly understood. […] In a very early report, it was mentioned that nearly 10% to 30% of women with uterine fibroids had faced with obstetric complications. […] The mechanism by which fibroids cause spontaneous abortion is unclear. Increased uterine irritability and contractility with the compressive effect of fibroids can compromise the blood supply of the decidua and the developing placenta. […] The locations of the fibroids such as submucosal, retroplacental and intramural close to the endometrial cavity (with proximity up to 2 mm) were reported to have independent risk for placental detachment.

• #85 The meaning and management of uterine fibroids in pregnancy: a narrative review of the literature – Gemici – Gynecology and Pelvic Medicine

  https://gpm.amegroups.org/article/view/9358/html

  Uterine fibroids are the clonal formation of the mesenchimal cell line that turns into tumor formation in either location (submucous, intramural, subserous and serous) at the uterus. […] The relationship between uterine fibroids and adverse pregnancy outcome is not clearly understood. […] In a very early report, it was mentioned that nearly 10% to 30% of women with uterine fibroids had faced with obstetric complications. […] The mechanism by which fibroids cause spontaneous abortion is unclear. Increased uterine irritability and contractility with the compressive effect of fibroids can compromise the blood supply of the decidua and the developing placenta. […] The locations of the fibroids such as submucosal, retroplacental and intramural close to the endometrial cavity (with proximity up to 2 mm) were reported to have independent risk for placental detachment.

• #86 Uterine Fibroids – The Oncofertility Consortium

  https://oncofertility.msu.edu/non-malignant-conditions/uterine-fibroids/

  Uterine fibroids are benign monoclonal tumors arising from smooth muscle cells of the myometrium. […] Proposed mechanisms include interference with implantation, uterine distention, or contractility. […] Fibroids that distort the uterine cavity are more likely to impact fertility, as well as in vitro fertilization (IVF) outcomes. […] For example, women with submucosal or intramural fibroids that protrude into the uterine cavity are found less likely to become pregnant with increased risk of spontaneous abortion. […] Subserosal fibroids, in contrast, do not affect fertility outcomes. […] In regards to IVF outcomes, one study demonstrated that having an intramural fibroid essentially halves the chance of an ongoing pregnancy following assisted conception. […] However, it should be noted that certain fibroid treatments can subsequently impact future pregnancy. […] Uterine artery embolization (UAE), for example, has higher rate of miscarriage and preterm delivery, compared to myomectomy. […] Thus, myomectomy is the preferred surgical therapy for women who wish to conceive.

• #87 Uterine Fibroids – The Oncofertility Consortium

  https://oncofertility.msu.edu/non-malignant-conditions/uterine-fibroids/

  Uterine fibroids are benign monoclonal tumors arising from smooth muscle cells of the myometrium. […] Proposed mechanisms include interference with implantation, uterine distention, or contractility. […] Fibroids that distort the uterine cavity are more likely to impact fertility, as well as in vitro fertilization (IVF) outcomes. […] For example, women with submucosal or intramural fibroids that protrude into the uterine cavity are found less likely to become pregnant with increased risk of spontaneous abortion. […] Subserosal fibroids, in contrast, do not affect fertility outcomes. […] In regards to IVF outcomes, one study demonstrated that having an intramural fibroid essentially halves the chance of an ongoing pregnancy following assisted conception. […] However, it should be noted that certain fibroid treatments can subsequently impact future pregnancy. […] Uterine artery embolization (UAE), for example, has higher rate of miscarriage and preterm delivery, compared to myomectomy. […] Thus, myomectomy is the preferred surgical therapy for women who wish to conceive.

• #88 Uterine Fibroids – The Oncofertility Consortium

  https://oncofertility.msu.edu/non-malignant-conditions/uterine-fibroids/

  Uterine fibroids are benign monoclonal tumors arising from smooth muscle cells of the myometrium. […] Proposed mechanisms include interference with implantation, uterine distention, or contractility. […] Fibroids that distort the uterine cavity are more likely to impact fertility, as well as in vitro fertilization (IVF) outcomes. […] For example, women with submucosal or intramural fibroids that protrude into the uterine cavity are found less likely to become pregnant with increased risk of spontaneous abortion. […] Subserosal fibroids, in contrast, do not affect fertility outcomes. […] In regards to IVF outcomes, one study demonstrated that having an intramural fibroid essentially halves the chance of an ongoing pregnancy following assisted conception. […] However, it should be noted that certain fibroid treatments can subsequently impact future pregnancy. […] Uterine artery embolization (UAE), for example, has higher rate of miscarriage and preterm delivery, compared to myomectomy. […] Thus, myomectomy is the preferred surgical therapy for women who wish to conceive.

• #89 Uterine fibroids (leiomyomas): Histology and pathogenesis – UpToDate

  https://www.uptodate.com/contents/uterine-fibroids-leiomyomas-histology-and-pathogenesis

  Uterine fibroids (leiomyomas) are the most common pelvic neoplasm in females. They are nonmalignant monoclonal tumors arising from the smooth muscle cells of the myometrium. The pathogenesis of leiomyomas is not well understood. Genetic predisposition, environmental factors, steroid hormones, and growth factors important in fibrotic processes and angiogenesis all play a role in the formation and growth of uterine fibroids. […] Leiomyoma-related effects on the function and structure of the endometrium are the final common pathways in the pathogenesis of excessive bleeding in myomatous uteri, and there is evidence of both histologic changes in the endometrium and endometrial vasculature in these uteri. […] The pathogenesis of uterine leiomyomas is reviewed here. At least two distinct components contribute to leiomyoma development.

• #90 Uterine Fibroids: Pathogenesis and Interactions with Endometrium and Endomyometrial Junction

  https://pmc.ncbi.nlm.nih.gov/articles/PMC3791844/

  Uterine leiomyomas (fibroids or myomas) are benign tumors of uterus and clinically apparent in a large part of reproductive aged women. […] To date, several pathogenetic factors such as genetics, microRNA, steroids, growth factors, cytokines, chemokines, and extracellular matrix components have been implicated in the development and growth of leiomyoma. […] Nowadays, conflicting data about the pathogenesis of leiomyomas coexist in the literature. The development of uterine myomas can be linked to predisposing risk factors, initiators and genetic mechanisms, promoters, and effectors. […] Even if many risk factors suggested by epidemiologic studies have linked uterine leiomyomas to the effects of estrogens and progesterone levels and their metabolism, other mechanisms may be involved in fibroids pathogenesis.

• #91 Uterine Fibroids: Pathogenesis and Interactions with Endometrium and Endomyometrial Junction

  https://pmc.ncbi.nlm.nih.gov/articles/PMC3791844/

  The authors measured the growth of fibroids in black and white women with clinically relevant fibroids using MRI technology; they demonstrated that fibroids within the same woman often have different growth rates despite having a similar hormonal milieu. […] It has been generally accepted that myomas are more prevalent in blacks than in Caucasian and Hispanic populations. […] Recently, some authors reported a statistically significant inverse correlation between serum 25-(OH) Vit D levels and fibroid prevalence in black subjects. […] Leppert et al. reported that the pathogenesis of fibroids seems to involve a positive feedback loop between extracellular matrix production and cell proliferation, and vitamin D might act to block the positive feedback. […] Several theories about the initiators of fibroids have been proposed.

• #92 Uterine fibroids (leiomyomas): Histology and pathogenesis – UpToDate

  https://www.uptodate.com/contents/uterine-fibroids-leiomyomas-histology-and-pathogenesis/print

  Uterine fibroids (leiomyomas) are the most common pelvic neoplasm in females. They are nonmalignant monoclonal tumors arising from the smooth muscle cells of the myometrium. The pathogenesis of leiomyomas is not well understood. Genetic predisposition, environmental factors, steroid hormones, and growth factors important in fibrotic processes and angiogenesis all play a role in the formation and growth of uterine fibroids. […] The disease is heterogeneous, and different fibroids within the same uterus may have different etiologies and arise from different somatic mutations. […] Leiomyoma-related effects on the function and structure of the endometrium are the final common pathways in the pathogenesis of excessive bleeding in myomatous uteri, and there is evidence of both histologic changes in the endometrium and endometrial vasculature in these uteri. […] The pathogenesis of uterine leiomyomas is reviewed here. At least two distinct components contribute to leiomyoma development.

• #93 New Insights into Molecular Pathogenesis of Uterine Fibroids: From the Lab to a Clinician-Friendly Review | IntechOpen

  https://www.intechopen.com/chapters/1165825

  The presence of steroid hormones stimulates the secretion of Wnt ligands from mature myometrium or leiomyoma cells. […] The activation of canonical Wnt pathway (-catenin-dependent) stimulates the differentiation of resting fibroblasts into myofibroblasts and has a key role in fibrotic processes, such as myoma development. […] In summary, molecular events in myoma biology are regulated through a complex network of interconnected and convergent, intracellular, extracellular, and intercellular pathways. Each pathway does not work on its own but it is a complicated network of molecular processes, although several signal transduction pathways converge into a final pathway.

• #94 New Insights into Molecular Pathogenesis of Uterine Fibroids: From the Lab to a Clinician-Friendly Review | IntechOpen

  https://www.intechopen.com/chapters/1165825

  The presence of steroid hormones stimulates the secretion of Wnt ligands from mature myometrium or leiomyoma cells. […] The activation of canonical Wnt pathway (-catenin-dependent) stimulates the differentiation of resting fibroblasts into myofibroblasts and has a key role in fibrotic processes, such as myoma development. […] In summary, molecular events in myoma biology are regulated through a complex network of interconnected and convergent, intracellular, extracellular, and intercellular pathways. Each pathway does not work on its own but it is a complicated network of molecular processes, although several signal transduction pathways converge into a final pathway.

• #95 Uterine Fibroids: Pathogenesis and Interactions with Endometrium and Endomyometrial Junction

  https://pmc.ncbi.nlm.nih.gov/articles/PMC3791844/

  Another interesting theory underlines that the pathogenesis might be similar to a response to injury; ischemic damage could be linked to release of increased vasoconstrictive substances at the time of the menses. […] Historically, uterine leiomyomata have not been considered a genetic disease. However much recent clinical evidence indicates that at least some myomata have a genetic etiology. […] Recent studies described that 70% of fibroids contained a series of mutations in a transcriptional regulator complex subunit 12 (MED12). […] Research for the pathogenesis of fibroids and abnormal extracellular matrix (ECM) led to the analysis of a growth factor with profibrotic activity, transforming growth factor (TGF-). […] Epigenetic changes have also been implicated in leiomyoma formation.

• #96 Uterine Fibroids: Pathogenesis and Interactions with Endometrium and Endomyometrial Junction

  https://pmc.ncbi.nlm.nih.gov/articles/PMC3791844/

  Uterine leiomyoma growth is strictly related to estrogens and their receptors. […] Leiomyoma growth is influenced by progesterone interaction with some growth factors; it upregulates the EGF (mitogenic) and transforming growth factor- (TGF-)3 (bimodal action). […] Several growth factors, such as vascular endothelial growth factor (VEGF), EGF, heparin binding epidermal growth factor (HB-EGF), PDGF, IGF, TGF-, TGF-, acidic fibroblast growth factor (aFGF), and basic fibroblast growth factor (bFGF), and their respective receptors have been demonstrated to play a role in leiomyoma growth. […] Many cytokines, including tumor necrosis factor-, erythropoietin, interleukin- (IL-)1, and IL-6, have been implicated in development of uterine leiomyoma. […] Extracellular disorganized matrix is a peculiar characteristic of fibroid growth, mainly consisting of collagen subtypes, fibronectin, and proteoglycans. […] The etiopathology of uterine fibroid remains unclear, multifactorial, and enigmatic. […] Abnormal ECM expression, increased growth factors, cytokines and chemokines concentrations, and an extracellular disorganized matrix have been implicated in development and growth of uterine leiomyomas.

• #97

  https://en.aig-journal.ru/articles/Etiopatogeneticheskie-mehanizmy-razvitiya-miomy-matki.html

  Uterine fibroids have a complex, multifactorial nature. Genetic, epigenetic factors, dysregulation of key signaling pathways involved in cell proliferation, apoptosis, extracellular matrix proliferation, as well as reactions to steroid hormones play an important role in the development and growth of myoma nodes. […] Modern views on the etiopathogenesis of uterine fibroids indicate that this disease has a complex, multifactorial nature. The development of this disease involves genetic and epigenetic mechanisms, reactions to steroid hormones, dysregulation of key signaling pathways, etc. However, in spite of significant progress in understanding of uterine fibroids pathophysiology, today there are still more questions than answers.

• #98 Update on the Role and Regulatory Mechanism of Extracellular Matrix in the Pathogenesis of Uterine Fibroids

  https://www.mdpi.com/1422-0067/24/6/5778

  Numerous studies demonstrated that TGF-β signaling plays an important role in the pathogenesis of UFs. […] Abnormal ECM accumulation and deposition have been shown to be associated with the activation of TGF-β signaling in UFs. […] The ECM acts as a reservoir of profibrotic growth factors and enhances their activity by increasing their stability and prolonging signaling duration. […] The significant variations in the quantity and distribution of the ECM also create variation in the degree of UF tissue stiffness from soft to firm to solid to hard, with a major impact on the gene expression and biology of these tumor lesions. […] Pharmacological drugs can suppress the UF phenotype by inhibiting ECM production via multiple mechanisms, including epigenetics. […] The deep mechanistic and functional investigation will help us better understand the regulatory mechanism of ECM-secreted cell types, cell–cell interaction, and environmental impacts on the risk and development of UFs.

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